The objectives of this research proposal are (1) to induce reproducible major phase differences in the circadian rhythms in mitosis and DNA synthesis between normal and neoplastic cells in the same tumor-bearing host by a single injection of isoproterenol (IPR); (2) to correlate the IPR phase-shifted rhythms in mitosis and DNA synthesis with circadian rhythms in mortality to cytosine arabinoside and X-irradiation in IPR phase-shifted animals; and (3) to treat such phase-shifted tumor-bearing hosts with X-irradiation and/or cytosine arabinoside at the point in time after IPR treatment when the tumor will be most susceptible and the host most resistant to the therapy. Mitotic indices and the incorporation of 3H-thymidine will be monitored at frequent intervals for 50 hours after a single injection of IPR or saline. The normal tissues monitored will be the corneal epithelium and the renewing cells in the epithelium of the small intestine and the bone marrow from both non-tumor-bearing and tumor-bearing hosts. Two different tumors, the Ehrlich ascites carcinoma and the L1210 leukemia, will also be monitored for rhythmic patterns for 50 hours after the single IPR or saline injection. Mortality rhythms for lethal doses of X-irradiation and cytosine arabinoside will be generated in IPR and saline-injected animals. A correlation of the data obtained will identify the point or points in time after the IPR treatment when cytosine arabinoside and/or X-irradiation can be given with resulting maximal toxicity to the tumor and minimal toxicity to the IPR-protected host. The most important general finding which is expected to emerge from the research is that circadian variables, such as mitosis and DNA synthesis, in both normal and neoplastic cell populations can be predictably and firmly forced out of phase. With such major phase differences induced between normal and neoplastic cells, significant selective toxicity of the tumor will be attainable.